1. Technical Field
The present invention is directed to an efficient process for the manufacture of (E)-4-N,N-dialkylamino crotonic acid in HX salt form of formula I
wherein R1 and R2 independently denote C1-3-alkyl groups and X− denotes an acid anion, such as the chloride, bromide, tosylate, mesylate or trifluoroacetate anion, with high quality, and a process for synthesis of EGFR tyrosine kinase inhibitors with heterocyclic quinazoline, quinoline or pyrimidopyrimidine core structure, using an acid addition salt I and activated derivatives thereof as intermediates.
2. Background Information
Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors have been studied clinically to demonstrate efficacy in treating certain cancers. Compounds which inhibit signal transduction by tyrosine kinases, for example of the human EGF receptor, have been shown to be useful for treating pathophysiological processes caused by hyperfunction of tyrosine kinases. David W. Fry, Pharmacol. Ther. Vol. 82, Nos. 2-3, pp. 207-218, 1999. Several irreversible inhibitors have been shown to have therapeutic advantages such as prolonged tumor suppression compared to reversible inhibitors such as gefitinib. DeBono & Rowinsky, Br. Med. Bull. 64:227-254 (2002).
The compounds of formula I and the salts thereof are suitable as a valuable intermediates in the synthesis of EGFR tyrosine kinase inhibitors based on a quinazoline, quinoline or pyrimidopyrimidine core structure. Examples of such EGFR tyrosinekinase inhibitors are HKI-272 (INN: Neratinib, in phase III clinical development for treatment of breast cancer), BIBW 2992 (INN: Afatinib, approved in the US and Europe for the treatment of non-small cell lung cancer patients with tumors bearing EGFR mutations), EKB-569 (INN: Pelitinib) or HKI 357.
BIBW 2992 is disclosed specifically in WO 02/50043. This compound is a highly selective, potent, irreversible dual inhibitor of erbbl receptor (EGFR) and erbB2 (Her2/neu) receptor tyrosine kinases, suitable for the treatment of e.g. benign or malignant tumours, particularly tumours of epithelial and neuroepithelial origin, metastasis and the abnormal proliferation of vascular endothelial cells (neoangiogenesis), for treating diseases of the airways and lungs which are accompanied by increased or altered production of mucus caused by stimulation by tyrosine kinases, as well as for treating diseases of the gastrointestinal tract and bile duct and gall bladder which are associated with disrupted activity of the tyrosine kinases. Promising effects in treatment of non-small cell lung cancer (NSCLC) patients have been reported already in Drugs of the Future 2008, 33(8): 649-654; and by Li, D. et al, in Oncogene (2008) 27, 4702-4711.
Pharmaceutical formulations of the compound are disclosed in the documents cited hereinbefore and in WO 2009/147238, indications to be treated and combination treatments are disclosed in WO 2007/054550 and WO 2007/054551. Skin toxicity and diarrhea are the most common adverse events in patients with adenocarcinoma of the lung and activating EGFR mutations, treated with this class of compounds (Mukherji, D., et al, Expert Opin. Investig. Drugs (2009) 18(3), 293-300).
Methods for the preparation of BIBW 2992 are described in WO 02/50043, WO 2005/037824 and WO 2007/085638.
WO 2002/50043 discloses a method of production in which aminocrotonylamino-substituted quinazolines are prepared in a one-pot reaction from the corresponding aniline component, bromocrotonic acid, oxalyl chloride and a secondary amine (Scheme 1).

The process is not well suited to technical use on an industrial scale, as the yields obtained are at most 50% and as a rule laborious purification by column chromatography is needed. Moreover the educt bromocrotonic acid is not commercially available in large amounts and the corresponding methyl bromocrotonate is only available with a purity of about 80%.
WO 2005/037824 discloses a method of preparation wherein BIBW 2992 is prepared using a Wittig-Horner-Emmons like process wherein the corresponding aminoquinazoline is reacted with diethylphosphonoacetic acid after activation to form a quinazoline substituted in 6-position by a carbamoyl-diethylphosphonate group, which is reacted in a second step with 2-dialkylaminoacetaldehyde or a corresponding aldehyde equivalent such as a corresponding acetale to form the unsaturated side chain in position 6 (Scheme 2).

WO 2007/085638 discloses an improved variant of the Wittig-Horner-Emmons like process described in WO 2005/037824 which uses a hydrogen sulphite adduct of formula
wherein M+ denotes a cation or a proton, instead of the 2-dialkylaminoacetaldehyde or aldehyde equivalent for the reaction with the quinazoline-6-carbamoyl-diethylphosphonate.
WO 2010/048477 discloses methods for manufacturing certain 4-amino-3-quinolinecarbonitrile derivatives, such as HKI-272, using stabilized 4-(amino)-2-butenoyl chloride intermediates (for example, 4-(dimethylamino)-2-butenoyl chloride) for coupling a 4-(amino)-2-butenoyl group to an amino group (—NH2) at the 6- or 7-position of a 4-amino-3-quinolinecarbonitrile. WO 2004/066919 and WO 2006/127207 both disclose preparation of 4-(dialkylamino)-2-butenoyl chloride by reaction of N,N-dialkylamino crotonic acid hydrochloride with oxalylchloride and subsequent amid coupling of 4-(dialkylamino)-2-butenoyl chloride with 4-amino-3-quinolinecarbonitrile.
Different routes to compound I or salts thereof are known in the art, but they all suffer from severe drawbacks from a commercial manufacturing point of view. They also do not allow for the control of the quality of the product in a way that is requested for the production of pharmaceutical intermediates. Therefore it was necessary to develop a novel route to compound I circumventing these problems.
As a very important intermediate in drug synthesis, different synthetic routes were developed to manufacture compound I. Most commonly the substitution between a dialkylamine with (E)-4-bromocrotonate was utilized as the key synthesis strategy.
In WO 2004/066919 two routes are documented employing brominated compounds A and E as key intermediates, as shown in Scheme 3.

Regarding the route starting with compound A, only about 30% total yield was achieved for overall two steps, and the purity of obtained compound I was insufficient (92%) for pharmaceutical production purpose. This is mainly due to the reasons, first, that purity of commerically available compound A is only very moderate, and, second, that hydrolysis occuring under basic conditions easily leads to by-products. Both drawbacks render final purification very difficult and cause low efficiency.
In the alternative route starting with compound C, some severe problems need to be solved before scale-up. These problems are, first, the use of highly toxic solvent CCl4, and, second, the silane reagent which may block the waste gas combustion system by the formation of sand.
WO 2010/131921 (corresponding to US 2012046494 A1) discloses an improved process for preparation of compound I providing better quality compared to the process according to WO 2004/066919. This improvement could be achieved by using compound H in high quality and performing hydrolysis of compound J under acidic conditions (Scheme 4). However, this process suffers from several issues with regard to scale up such as, first, the use of bromine which should be avoided in production scale, second, the use of large amounts of environment-unfriendly solvent dichloromethane, third, extensive work required to obtain pure compound H which needs vacuum distillation, and, fourth, tedious work to distill off great amounts of water during the hydrolysis step, e.g. about 7 ml of water to obtain 1 g of compound H.
All those issues together with the linear synthetic strategy (total yield was around 38%) lead to high expenditure regarding Volume-Time-Output and consequently less competitive.

In the light of the above disadvantages of the known methods of production there was a strong need for a novel or improved process to manufacture the compounds of formula I and the salts thereof. Thus the aim of the present invention is to provide a process which allows the synthesis of the desired product on commercial scale with high quality and in a competitive manner, using highly pure starting materials which are readily available and without any high technical expenditure. Preferably the process according to the invention should be environment friendly and sustainable, avoiding toxic reactants or solvents as well as complex, expensive or time-consuming purification processes and energy consuming reaction steps. As a matter of course, the process of the invention should provide the compounds of formula I and the salts thereof in a quality suitable for use in production of pharmaceuticals according to GMP standards, especially for use in production of EGFR tyrosine kinase inhibitors based on a quinazoline, quinoline or pyrimidopyrimidine core structure.